Ciprofloxacin and sparfloxacin penetration into human brain tissue and their activity as antagonists of GABAA receptor of rat vagus nerve.

Patients undergoing elective surgery for removal of brain tumors, aneurysms, or other vascular malformations were administered a single oral dose of sparfloxacin (400 mg; 16 patients) or ciprofloxacin (750 mg; 5 patients) either 3 to 5 h or 22 to 26 h before surgery. Serum samples were taken from all patients at 0, 1, 3 to 5, 7 to 9, and 22 to 26 h after dosing; an additional serum sample was obtained at 48 h from patients who received sparfloxacin. A single sample of brain tissue was taken from all patients; a sample of cerebrospinal fluid (CSF) uncontaminated with blood was obtained from five patients. Serum and brain tissue samples were assayed by high-pressure liquid chromatography. Drug concentrations in brain tissue exceeded those in CSF by 1.8- to 19.4-fold. Kinetic modeling suggested that peak sparfloxacin concentrations in brain tissue may have occurred later than 3 to 5 h and that actual peak concentrations may therefore have been higher (up to 10 micrograms/g of tissue). The activities of ciprofloxacin and sparfloxacin as antagonists of the gamma-aminobutyric acid antagonist (GABAA) receptor were measured with the rat vagus nerve preparation. The 50% inhibitory concentration (IC50) of ciprofloxacin was 250 microM (95.25 micrograms/ml), but in the presence of biphenyl acetic acid (BPAA), the IC50 of ciprofloxacin was only 0.6 microM (0.23 microgram/ml). In contrast, the IC50 of sparfloxacin alone or in the presence of BPAA was > 300 microM (> 100 micrograms/ml). We conclude that the concentrations of ciprofloxacin and sparfloxacin in brain tissue may exceed serum drug concentrations and cannot be predicted from the concentrations in CSF. Sparfloxacin does not have any activity as a GABA antagonist, either alone or in the presence of BPAA, at the concentrations which are likely to be reached in human brain tissue.     

A regional audit of the investigation and treatment of colorectal and pelvic floor disorders (1984–1991)

The activities of a regional physiology unit established for the investigation of colorectal and pelvic floor physiology in health and disease in a clinically relevant setting has been audited and its evolution described over a period of eight years. Trends in surgical treatment of some of these disorders over the same period have also been documented in the Lothian Region. Although there has been little change in the number of patients investigated annually patterns of investigation appear to change. Sphincter manometry, proctometrography and somatosensory reflex measurements have remained the most frequently performed and useful investigations. Spinal stimulation studies increased transiently because of a collaborative investigation of bowel, and bladder function in patients with spinal injuries. A considerable increase in surface EMG tests and dynamic proctography has occurred. These trends are thought to be related to interest in defining evacuation dysfunction of the rectum and related problems of the pelvic floor. Isotope proctography now rivals barium videoproctography; at the same time the use of manometric colonic motility studies has diminished. Anal ultrasonography has replaced sphincter mapping in the last year and is being applied to other aspects of anorectal pathology. The last 4 years have seen the introduction and increasing use of non-surgical therapeutic modalities for the treatment of faecal incontinence and constipation: reflex electronic sphincter stimulation, biofeedback and the use of a prokinetic agent to promote colonic motility. Concomitant changes in the surgery of constipation and reconstructive anorectal procedures have been observed. It is recommended that coloproctology units should have easy access to at least one such investigation laboratory within their catchment area together with appropriate auditing facilities.

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Résumé Les activités d'une unité régionale de physiologie destinées à l'investigation de la physiologie colo-rectale et du plancber pelvien chez les sujets sains et malades dans un contexte clinique adéquat a été l'objet d'un audit et son évolution décrite sur une période de 8 ans. Les tendances dans le traitement chirurgical de certains de ces désordres ont été aussi étudiées dans la même période. Bien qu'il y ait eu peu de changement dans le nombre des patients étudiés chaque années, l'aspect des explorations semble changé. La manométrie sphinctérienne, la proctométrographie et la mesure des réflexes somato-sensitifs sont restés les examens les plus utiles et les plus fréquemment utilisés. Les études de la stimulation spinale ont augmenté transitoirement en raison d'une étude en collaboration des fonctions intestinale et vésicale chez les patients ayant un traumatisme médullaire. L'augmentation considérable de l'électromyographie de surface et de la proctographie dynamique est survenue. Ces tendances sont dûes probablement à l'intérêt qu'il y a à définir les disfonctions d'évacuation rectale et les problèmes en relation avec le plancher pelvien. La proctographie isotopique est maintenant en rivalité avec la vidéo-proctographie au barium. Pendant ce temps l'utilisation des études de la motilité colique par manométrie ont diminué. L'échographie endo-rectale a remplacé la cartographie sphinctérienne dans la dernière année et a tendance à être utilisée pour les autres aspects de la pathologie ano-rectale. Les 4 dernières années ont vu l'introduction et l'utilisation croissante des thérapeutiques non chirurgicales pour le traitement de l'incontinence fécale et de la constipation: stimulation reflexe sphinctérienne électronique, biofeedback et utilisation d'agents prokinétiques pour augmenter la motricité colique. Des changements concomitants dans la chirurgie de la constipation et de la reconstruction ano-rectale ont été observés. Il est recommandé que les unités de proctologie puissent avoir un accés facile à au moins un tel laboratoire d'investigations dans leur aire de travail en même temps que des facilités appopriées de vérification.

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Paper read in part at the Annual Meeting of the Association of Coloproctology of Great Britain and Ireland, Southampton, June 1992     

Effects of isolated interventricular septal ischemia on global and segmental function of the canine right and left ventricle

The effects of isolated septal artery ligation were studied in 17 dogs. Contraction of the interventricular septum (IVS) and the free walls of both ventricles was measured by implanting ultrasonic crystals. Global ventricular function was assessed by Starling function curves. Following septal artery ligation, IVS shortening was immediately replaced by systolic lengthening. Thirty minutes after septal artery ligation, the right ventricular (RV) stroke work (SW) was significantly depressed at end-diastolic pressure (EDP) of 7 and 8.5 mm Hg from control values of 7.6 ± 0.4 and 8.6 ± 0.6 gmM to 6.7 ± 0.4 and 7.4 ± 0.5gmM respectively. However, LVSW after septal artery ligation was similar to control values for EDP from 5 to 19 mm Hg. These changes were associated with unchanged RV free wall movement of 21 ± 3% in the inflow region and 23 ± 5% in the outflow region. LV free wall systolic shortening following septal artery ligation increased by 16 ± 3%. It is concluded that canine septal artery ligation causes global dysfunction of the RV but not of the LV.     

Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair.     

Survival analysis according to treatment modality in pancreatic cancer patient]

BACKGROUND/AIMS: Pancreatic cancer is the 5(th) leading cause of cancer death in Korea and its incidence is increasing. At present, surgical resection offers the best chance of cure. However, most of pancreatic cancers are already unresectable at initial diagnosis. Thus, the majority of patients depend on chemotherapy, radiotherapy, or supportive care. We investigated the effect of treatment modalities on the survival in pancreatic cancer. METHODS: Between September 1994 and May 2003, one hundred and fifty four patients with pancreatic cancer were treated by surgery, radiotherapy, chemotherapy or conservative management. The clinical datas were analyzed retrospectively for survival according to stage and treatment modality. RESULTS: Overall median survival time was 5.7 months and 1 year survival rate was 18.3%. In patients with stage I to III disease, the median survival time was 13.9 months in surgery group, 10.2 months in radiation group, and 6.1 months in supportive care group (p%lt;0.01). Survival rate according to treatment modality was significantly different among groups. In patients with stage IV disease, the median survival time was 6.1 months in radiation therapy group, 7.1 months in chemotherapy group, and 2.7 months in supportive care group. Overall survival was significantly higher in treatment groups than in supportive care group (p<0.01), but there was no difference in survival between chemotherapy group and radiotherapy group. CONCLUSIONS: In patients with stage I to III pancreatic cancer, surgery can improve median survival. In patients with stage IV, either chemotherapy or radiotherapy can prolong survival compared to supportive care. These results suggest that more active treatment of pancreatic cancer even in advanced stage will be needed to prolong the survival.     

Quantitative comparison of thallium-201 scintigraphy after exercise and dipyridamole in coronary artery disease

Data comparing myocardial thallium-201 imaging after exercise and intravenous dipyridamole infusion in the same patients are scarce. Accordingly, this study is a segment-by-segment quantitative analysis of regional uptake and washout of thallium-201 after dipyridamole (0.56 mg/kg) and symptom-limited exercise testing in 21 patients (ages 58 +/- 9.2 years) with chest pain studied 2.5 +/- 1.0 weeks apart. Thallium-201 activity in 9 myocardial segments was measured in initial and delayed anterior and 45 degree left anterior oblique views, producing 184 pairs of segments in the distribution of 63 coronary supply regions for direct comparison. The number of segments with normal thallium-201 uptake and the number of numerically significant defects were similar with exercise and dipyridamole (76 vs 73%, 24 vs 27%, respectively, difference not significant). A slightly higher proportion of redistribution defects was found after dipyridamole infusion compared to exercise (17 vs 10%, p less than 0.05). Agreement between 87% (165 of 189) of segment pairs was found when each was classified as either normal or abnormal. Although 24 of 189 segments were discordant, agreement was observed in 92% (61 of 63) of coronary supply regions determined to be normal (41 of 41) or abnormal (20 of 22). In 15 patients who underwent cardiac catheterization, exercise and dipyridamole-thallium-201 scintigraphy detected 61% (16 of 26) vs 61% (16 of 26) of stenoses greater than 50% (difference not significant) and 100% (19 of 19) vs 100% (19 of 19) (difference not significant) normal vessels, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

The zebrafish spi1 promoter drives myeloid-specific expression in stable transgenic fish

The spi1 (pu.1) gene has recently been identified as a useful marker of early myeloid cells in zebrafish. To enhance the versatility of this organism as a model for studying myeloid development, the promoter of this gene has been isolated and characterized. Transient transgenesis revealed that a 5.3 kilobase promoter fragment immediately upstream of the spi1 coding sequence was sufficient to drive expression of enhanced green fluorescent protein (EGFP) in injected embryos in a manner that largely recapitulated the native spi1 gene expression pattern. This fragment was successfully used to produce a germ line transgenic line of zebrafish with EGFP-expressing myeloid cells. These TG(spi1:EGFP)pA301 transgenic zebrafish represent a valuable tool for further studies of myeloid development and its perturbation.     

Relation of blood urea nitrogen to long-term mortality in patients with heart failure

Patients with chronic kidney disease and heart failure (HF) have been shown to be at higher risk for major adverse cardiovascular events and death. Recent studies have demonstrated that blood urea nitrogen (BUN) might serve as a powerful predictor of mortality in acutely decompensated HF. The goal of this study was to determine the impact of BUN on long-term mortality in patients with stage B and C HF. Our retrospective analysis included patients undergoing percutaneous intervention with a calculated left ventricular ejection fraction < or =50%. Patients on dialysis or with technically inadequate left ventriculograms were excluded. Chart review was performed and mortality data were obtained. Our population included 444 patients with a mean ejection fraction of 38 +/- 10%, mean age of 59 +/- 11 years, median BUN of 14 mg/dl, and median glomerular filtration rate (GFR) of 81 ml/min/1.73 m(2); 31% had stage C HF, and 33% died during follow-up. Patients with increased BUN (> or =17 mg/dl) and decreased GFR (< or =69 ml/min/1.73 m(2)) had significantly increased long-term mortality on Kaplan-Meier analysis (8-year mortalities of 57% and 55%, respectively). In patients with stage C HF, mortalities at 8 years were 69% and 73% with abnormal BUN and GFR, respectively. Proportional hazard regression analysis demonstrated that BUN and stage C HF were independently associated with increased mortality, whereas GFR was not. In conclusion, we demonstrated that BUN is strongly associated with mortality in patients with stage B and C HF and may serve as a better biomarker than GFR for prognostication.     

Anti-laminin autoantibodies in collagen vascular diseases: the use of adequate controls in studies of autoimmune responses to laminin.

OBJECTIVES--To determine the significance of anti-laminin antibodies in patients with collagen vascular diseases using a large control population of normal individuals. METHODS--Anti-laminin antibodies of IgG isotypes were determined using an ELISA assay in a population consisting of 73 patients with systemic sclerosis, 10 with urticarial vasculitis, five with leukocytoclastic vasculitis, 13 with giant cell arteritis, and eight with dermatomyositis. Sera from 134 healthy individuals served as controls. RESULTS--Only eight sera in the systemic sclerosis group, one in the leukocytoclastic group and one in the giant cell arteritis group were abnormal. No other sera were abnormal. CONCLUSION--These data contradict previous studies using smaller numbers of controls. The necessity for an adequate control population to define abnormal when comparing immune responses among groups is frequently under-emphasised in rheumatological studies.